Citrate-Induced p85α–PTEN Complex Formation Causes G2/M Phase Arrest in Human Pharyngeal Squamous Carcinoma Cell Lines

International Journal of Molecular Sciences

Shih-Shun Chen¹  Shyang-Guang Wang¹  Meng-Liang Lin²  Kuang-Chen Hung³ 

[1] Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung 40601, Taiwan;Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan;Division of Neurosurgery, Department of Surgery, Taichung Army Force General Hospital, Taichung 41152, Taiwan;

关键词: Akt;    citrate;    cyclin B1;    CDK1;    p85α;    PTEN;    G₂/M;   

DOI  :  10.3390/ijms20092105

来源: DOAJ

【 摘 要 】

Citrate is a key intermediate of the tricarboxylic acid cycle and acts as an allosteric signal to regulate the production of cellular ATP. An elevated cytosolic citrate concentration inhibits growth in several types of human cancer cells; however, the underlying mechanism by which citrate induces the growth arrest of cancer cells remains unclear. The results of this study showed that treatment of human pharyngeal squamous carcinoma (PSC) cells with a growth-suppressive concentration of citrate caused cell cycle arrest at the G₂/M phase. A coimmunoprecipitation study demonstrated that citrate-induced cell cycle arrest in the G₂/M phase was associated with stabilizing the formation of cyclin B1−phospho (p)-cyclin-dependent kinase 1 (CDK1) (Thr 161) complexes. The citrate-induced increased levels of cyclin B1 and G₂/M phase arrest were suppressed by the caspase-3 inhibitor Ac-DEVD-CMK and caspase-3 cleavage of mutant p21 (D112N). Ectopic expression of the constitutively active form of protein kinase B (Akt1) could overcome the induction of p21 cleavage, cyclin B1−p-CDK1 (Thr 161) complexes, and G₂/M phase arrest by citrate. p85α−phosphatase and tensin homolog deleted from chromosome 10 (PTEN) complex-mediated inactivation of Akt was required for citrate-induced G₂/M phase cell cycle arrest because PTEN short hairpin RNA or a PTEN inhibitor (SF1670) blocked the suppression of Akt Ser 473 phosphorylation and the induction of cyclin B1−p-CDK1 (Thr 161) complexes and G₂/M phase arrest by citrate. In conclusion, citrate induces G₂/M phase arrest in PSC cells by inducing the formation of p85α−PTEN complexes to attenuate Akt-mediated signaling, thereby causing the formation of cyclin B1−p-CDK1 (Thr 161) complexes.

【 授权许可】

Unknown